The central neuromodulation of gastric secretion by bombesin (and bombesin-related peptides) and the new morphinomimetic peptide dermorphin were investigated using the laboratory rat as the model system. The intracerebral ventricular (icv) administration of bombesin regulates gastric secretion in pylorus-ligated rats; neutralizes gastric acidity, reduces hydrogen ion concentration, and decreases the volume of secretion. Only peptides closely resembling bombesin, such as alytesin and GRP (mammalian heptacosapeptide resembling bombesin) had comparable bioactivity. Indomethacin, a potent inhibitor of prostaglandin biosynthesis, prevented the bombesin-mediated effects when administered icv. These results suggest that the neuromediation of gastric secretion by bombesin involves the release of prostaglandins in brain. Dermorphin, an amphibian opiate-like heptapeptide containing a natural D-amino acid, effectively reduces gastric secretion when administered icv. The analysis of 19 homologues and analogues of dermorphin provided evidence on the sequence specificity of the neuroregulation of gastric acid output. The amino-terminal tetrapeptide amide provided the smallest biological active fragment (similar to the limit digestion product of dermorphin in a brain homogenate). The D-isomer of Ala residue at position 2 is indispensible for the retention of bioactivity. The dosages of dermorphin utilized to suppress gastric secretion were not only without effect on analgesia or catalepsy, but also the analogues displayed differential effects in respect to these physiological parameters. Thus, dermorphin acts centrally in the brain, presumably interacting with either mu receptors, or subtype thereof, to regulate gastric secretion.